3-heteroaryl-2-thio-1,3-thiazane-2,4-diones

ABSTRACT

3 - HETEROARYL - 2-THIO-1,3-THIAZANE-2,4-DIONES IN WHICH THE HETEROARYL MOIETY IS PYRIDYL, THIAZOLYL, THIENYL, FURYL, PYRIDAZINYL, THIADIAZOLYL, PYRIMIDYL OR TRIAZINYL AND HAVING ANTI-ARTHRITIC ACTIVITY ARE GENERALLY PREPARED VIA RING CLOSURE OF A B-(THIOCARBAMOYLTHIO) SUBSTITUTED CARBOXYLIC ACID WITH ACETIC ANHYDRIDE/CONCENTRATED SULFURIC ACID.

United States Patent Oflice 3,732,2163-HETEROARYL-2-THIO-1,3-Tl-IIAZANE-2,4-DIONES Joseph Weinstock,Phoenixville, Pa., assignor to Smith Kline & French Laboratories,Philadelphia, Pa. No Drawing. Filed Nov. 17, 1971, Ser. No. 199,768 Int.Cl. C07d 93/06 US. Cl. 260-243 R 4 Claims ABSTRACT OF THE DISCLOSURE 3heteroaryl 2-thio-1,3-thiazane-2,4-diones in which the heteroaryl moietyis pyridyl, thiazolyl, thienyl, furyl, pyridazinyl, thiadiazolyl,pyrimidyl or triazinyl and having anti-arthritic activity are generallyprepared via ring closure of a B- (thiocarbamoylthio) substitutedcarboxylic acid with acetic anhydride/concentrated sulfuric acid.

5 3N-Hetcroaryl FORMULA I wherein:

R R and R each represent hydrogen, methyl or phenyl, preferablyhydrogen;

R represents hydrogen or methyl, preferably hy drogen; and

Heteroaryl represents a 5- or 6-membered heterocyclic aromatic ringhaving 1, 2 or 3 hetero atoms, such as oxygen, sulfur or nitrogen,attached to the thiazane nitrogen via a carbon atom, for example 2-, 3-or 4-pyridyl, 6- methyl-Z-pyridyl, 5-chloro-2-pyridyl, 2- orS-thiazolyl, 2- or 3-thienyl, 2- or B-furyl, 3- or 4-pyridazinyl, 4 or5- (1,2,3-thiadiazolyl), 5-(l,2,4-thiadiazolyl), 3-(l,2,5-thiadiazolyl),2-(1,3,4-thiadozalyl), 2-, or 4- or S-pyrimidyl, 3- or 5-as-triazinyl or2-s-triazinyl.

The compounds of Formula I above are prepared by one of the followingsynthetic methods. An isothiocyanate of the formula heteroarylN=C=S iscondensed with a fi-mercapto substituted carboxylic acid of the formulaR3 R1 HSt'J-t'J-(JOOH in aqueous trimethylamine solution at roomtemperature to give a fl-(thiocarbamoylthio) substituted acid of theformula 4 R2 which is converted to the desired thiazane product byheating on a steam bath with acetic anhydride containing a few drops ofconcentrated sulfuric acid. The isothiocyanate starting materials areprepared, for example, by the reaction of the required heteroaryl aminewith thio- 3,732,216 Patented May 8, 1973 phosgene either in aqueoussolution or in an organic solvent.

Alternatively, starting with a dithiocarbamate, a compound of theformula preferably as a triethylamine salt, is condensed with B-propiolactone to give a fi-(thiocarbamoylthio)-propionic acid which isconverted to the desired thiazane product as described above. Thedithiocarbamate starting materials are prepared, for example, by thereaction of the required heteroaryl amine with carbon disulfide,preferably in the presence of triethylamine, at room temperature.

The compounds of this invention are administered in conventional dosageunit forms by incorporating an amount sufficient to produceanti-arthritic activity with a nontoxic pharmaceutical carrier accordingto accepted procedures. Preferably the dosage units will contain acompound of Formula I in an; amount of from about 25 mg. to about 400mg. per unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrups, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent includes anytime delay material well known to the art, such as glyceryl monostearateor glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlonzenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or an aqueous ornonaqueous liquid suspension.

The method of producing anti-arthritic activity in accordance with thisinvention comprises administering internally to an animal organism acompound of Formula I above, usually combined with a pharmaceuticalcarrier, in an amount sufiicient to produce anti-arthritic activitywithout limiting side effects. The active medicament will beadministered in a dosage unit, as described above, orally orparenterally, the oral route being preferred. Advantageously equal doseswill be administered one or two times daily with the daily dosageregimen being from about 25 mg. to about 800 mg. When the methoddescribed above is carried out, anti-arthritic activity is produced witha minimum of side effects.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingreclients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds of thisinvention and their incorporation into pharmaceutical compositions, andas such are not to be considered as limiting the invention set forth inthe claims appended hereto.

EXAMPLE 1 A mixture of 18.8 g. of Z-aminopyridine, 12 ml. of carbondisulfide and 30 ml. of triethylamine is warmed to give a clear solutionand shaken at room temperature for one and one-half hours. The solid istreated with ether to give triethylammoniumN-(Z-pyridyl)-dithiocarbamate (Knott, J. Chem. Soc. 1956, 1644-9).

To a suspension of 86.6 g. (0.32 m.) of the above preparedtriethylammonium salt in water is added 24.0 g. (0.34 m.) offi-propiolactone, with stirring at room temperature. The reactionmixture is stirred until homogeneous and then made acidic with glacialacetic acid. The resulting product is recrystallized from 50% aqueousacetic acid to give 3-[N-(2-pyridyl)-thiocarbamoylthio]- propionic acid,M.P. 159-162" C.

A mixture of 19.5 g. (0.0806 m.) of the above propionic acid, 300 ml. ofacetic anhydride and 3-4 drops of concentrated sulfuric acid is heatedon a steam bath until the reaction mixture is homogeneous. The volume isreduced to one-third and the solution is colored to give3-(Z-pyridyl)-2-thio-1,3-thiazane 2,4 dione, MP. 149 151' C.

Similarly the triethylammonium salts of N-(3-pyridyl)- dithiocarbamate,N-(4-pyridyl)-dithiocarba'mate, N (6- methyl-2-pyridyl)-dithiocarbamateand N chloro-2- pyridyl)-dithiocarbamate are reacted with8-propiolactone as described above followed by treatment of theresulting propionic acids with acetic anhydride to give 3 (3-pyridyl)-2-thio-1,3-thiazane-2,4 dione, 3 (4 pyridyl)-2-thio-l,3-thiazane-2,4-dione, 3-(6-methyl 2 pyridyl)-2-thio-1,3-thiazane-2,4-dione and 3-(5-chloro-2-pyridyl)-2-tl1io-1,3-thiazane-2,4-dione, respectively.

EXAMPLE 2 To a suspension of 88 g. (0.32 m.) of triethylammoniumN-(Z-thiazolyl)-dithiocarbamate in water is added 24.0 g. (0.34 m.) offl-propiolactone, with stirring at room temperature. Stirring iscontinued until the reaction mixture is homogeneous and it is then madeacidic with glacial acetic acid to yield the product B-[N-(Z-thiazolyD-thiocarbamoylthio]-propionic acid, M.P. 185-187 C.

A mixture of 20 g. (0.0806 In.) of the above propionic acid, 300 ml. ofacetic anhydride and 3-4 drops of concentrated sulfuric acid is heatedon a steam bath until the reaction mixture is a homogeneous solution.The latter is reduced to one-third volume and cooled to give 3-(2-thiazolyl)-2-thio 1,3 thiazane 2,4 dione, M.P. 153- 155 C.

EXAMPLE 3 Following the procedure of Example 1, triethylammoniumN-(Z-thienyl)-dithiocarbamate (obtained from 2- aminothiophene, carbondisulfide and triethylamine) is reacted with B-propiolactone in Water togive 8-[N-(2- thienyl)-thiocarbamoylthio]-propionic acid which is thensimilarly treated with acetic anhydride/concentrated sulfuric acid toyield 3-(2-th'ienyl)-2-thio-1,3-thiazane 2,4- dione.

Similarly, by employing triethylammonium N-(2- furyl)-dithiocarbamate asthe reactant and proceeding as above there is obtained3-(2-furyl)-2-thio-1,3-thiazane- 2,4-dione.

EXAMPLE 4 To a mixture of 13.7 g. (0.1 m.) of 2-pyrimidylisothiocyanate(obtained from 2-aminopyrimidine and thiophosgene) and 10.6 g. (0.1 m.)of fl-mercaptopropionic acid is added 100 ml. of 25% aqueoustrimethylamine with stirring. Stirring is continued at room temperaturefor 30 minutes until the reaction mixture becomes homogeneous and thenit is made acidic with concentrated hydrochloric acid to givep-[N-(Z-pyrimidyl)-thiocarbamoylthio]-propionic acid.

A mixture of 19.5 g. (0.08 m.) of the above propionic acid, 300 m1. ofacetic anhydride and 3-4 drops of concentrated sulfuric acid is heatedon a steam bath until homogeneous. The reaction mixture is reduced involume to one-third and cooled to yield 3-(2-pyrimidyl)-2-thio-1,3-thiazane-2,4-dione.

Similarly, by utilizing 3-pyridazinylisothiocyanate as the initialreactant as described above there is ultimately produced3-(3-pyridazinyl)-2-thi0-1,3-thiazane-2,4-dionc.

4 EXAMPLE 5 By following the procedures outlined in Example 1,triethylammonium N-[2-(1,3,4 thiadiazolyl)]-dithiocarbamate is reactedwith ,B-propiolactone in water to give the propionic acid derivativewhich is heated with acetic anhydride/concentrated sulfuric acid toyield 3-[2-(1,3,4 thiadiazolyl) ]-2-thio-1,3-thiazane-2,4-dione.

Similarly, by employing triethylammoniumN-(2-s-triazinyl)-dithiocarbamate as the initial reactant as describedabove there is obtained as the final product 3-(2- s-trazinyl -2-thiol,3-thiaZane-2,4-dione.

EXAMPLE 6 To a mixture of 13.6 g. (0.1 m.) of 2-pyridylisothiocyanate(obtained from 2-aminopyridine and thiophosgene) and 13.4 g. (0.1 m.) of3-mercapto-2,2-dimethylpropionic acid is added ml. of 25 aqueoustrimethylamine with stirring. Stirring is continued at room temperatureuntil the reaction mixture is homogeneous and then it is made acidicwith concentrated hydrochloric acid to give3-[N-(Z-pyridyl)-thiocarbamoylthio]-2,2-dimethylpropionic acid.

A mixture of 21.6 g. (0.08 m.) of the above propionic acid, 300 ml. ofacetic anhydride and 3-4 drops of concentrated sulfuric acid is heatedon a steam bath until homogeneous. The reaction mixture is reduced involume to one-third and cooled to give 3-(2-pyridyl) 5,5dimethyl-2-thio-1,3-thiazane-2,4-dione.

Similarly, by employing 3-mercapto-2-methylpropionic acid or3-mercapto-3-methylbutyric acid as the reactants as described abovethere are obtained the corresponding products, 3-(2-pyridyl)-5-methyl 2thio 1,3 thiazane- 2,4-dione and 3-(2-pyridyl)-6,6-dimethyl 2 thio 1,3-thiazane-2,4-di0ne, respectively.

EXAMPLE 7 Following the procedures of Example 6, Z-thiazolylisocyanate(obtained from Z-aminothiazole and thiophosgene) is reacted with3-mercapto-2,2-diphenylpropionic acid in aqueous trimethylamine to yield3-[N-(2-thiazolyl)-thiocarbamoylthio] 2,2 diphenylpropionic acid. Thelatter, with acetic anhydride/concentrated sulfuric acid, is convertedto the product3-(2-thiazolyl)-5,5-diphenyl-2-thio-1,3-thiazane-2,4-dione.

Similarly, reaction of 3-mercapto 2 phenylpropionic acid with2-thiazolylisocyanate as described above gives the correspondingpropionic acid derivative which furnishes upon treatment with aceticanhydride/ concentrated sulfuric acid the product3-(Z-thiazolyl)-5-phenyl-2-thio- 1,3-thiazane-2,4-dione.

EXAMPLE 8 'FOllOWlIlg the procedures of Example 6, 2-pyridylisocyanateis reacted with 3-mercaptobutyric acid (Berichte Chem. 74, 1758) in 25%aqueous trimethylamine to yield 3-[N (2 pyridyl) thiocarbamoylthio1-butyric acid. The latter, with acetic anhydride and 3-4 drops ofconcentrated sulfuric acid, is heated on the steam bath untilhomogeneous to give upon work-up,3-(2-pyridyl)-6-methyl-2-thio-1,3-thiazane-2,4-dione.

Similarly, reaction of fi-mercaptohydrocinnamic acid With2-pyridylisocyanate as described above gives the corresponding[3-[N-(2-pyridyl)-thiocarbamoylthio] hydrocinnamic acid which upontreatment with acetic anhydride/ concentrated sulfuric acid results inthe formation of the product 3-(2-pyridyl)-6-phenyl-2-thio-1,3-thiazane-2,4-di0ne.

EXAMPLE 9 Ingredients: Mg./tablet 3-(2-pyridyl)-2-thio-1,3-thiazane-2,4dione 50 Calcium sulfate, dihydrate Sucrose 25 Starch "a 15 Talc 5Stearic acid 3 The sucrose, calcium sulfate and thiazanedione arethoroughly mixed and granulated with hot 10% gelatin solution. Thewetted mass is passed through a #6 mesh screen directly onto dryingtrays. The granules are dried at 120 F. and passed through a #20 meshscreen, mixed with the starch, talc and stearic acid and compressed intotablets.

EXAMPLE 10 Ingredients: Mg./capsule3-(2-thiazolyl)-2-thio-1,3-thiazane-2,4-dione 100 Magnesium stearateLactose 350 The above ingredients are screened through a #40 meshscreen, mixed and filled into #0 hard gelatin capsules.

What is claimed is: 1. A chemical compound of the formula:

wherein R R and R are each hydrogen, methyl or phenyl; R is hydrogen ormethyl; and Heteroaryl is pyridyl, thiazolyl, thienyl, fury],pyridazinyl, thiadiazolyl, pyrimidyl or tirazinyl, said heteroaryl beingattached to the thiazane nitrogen via a a carbon atom. 2. A compoundaccording to claim 1 in Which R R R and R are hydrogen.

3. A compound according to claim 2 in which heteroaryl is 2-pyridyl.

4. A compound according to claim 2 in which heteroaryl is 2-thiazolyl.

JOHN M. FORD, Primary Examiner US. Cl. X.R.

